Insulin resistance is a risk factor for a variety of chronic diseases, including type 2 diabetes and cardiovascular disease. The IRAS Family Study is a multicenter project designed to study the genetic epidemiology of insulin resistance and adiposity. The IRAS Family Study was originally funded as six linked R01s in 1999. The recruitment and phenotyping components have been completed, greatly exceeding the original study goals. All families were of African-American or Hispanic descent. A total of 132 extended families (1861 subjects) have been studied for direct measures of glucose homeostasis (using the insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT)) and adiposity (by CT scan). These investigations have identified substantial genetic contribution to measures of glucose homeostasis (insulin sensitivity, glucose effectiveness, first-phase insulin response, disposition index, fasting glucose and fasting insulin) and adiposity (visceral fat, subcutaneous fat, BMI and waist circumference). A 10 cM genome scan of the IRAS Family Study DNA has been completed. Linkage analyses of the first set of 66 families (-1200 DNA samples) have identified several genomic regions related to glucose homeostasis and adiposity that are suitable for follow-up. Thus, the first component of this renewal application, entitled Genetics of Glucose Homeostasis, Fat, Inflammation & CVD, targets the further exploration of genomic regions and positional cloning of genes contributing to variation in glucose homeostasis and adiposity. The second component of this renewal focuses on the genetic epidemiology of new, critical phenotypes of atherosclerosis and inflammation. The following aims are proposed: (1) continue the process of positional cloning genes contributing to variation in glucose homeostasis and adiposity. Positional candidate genes will be identified. (2) Re-contact and study the original cohort for measurement of important, previously unmeasured, phenotypes of atherosclerosis (carotid intima-medial thickness) and inflammation (adhesion molecules and matrix metalloproteinases). Using the existing genome scan data and variance-components-based linkage analysis methods, regions of the genome will be detected that contribute to variation in these new phenotypes. The proposed study is unique in its performance of gene discovery for cardiovascular risk factors in a multi-ethnic (non-majority) sample while simultaneously examining the genetic and environmental correlations among these and other atherosclerosis phenotypes. [unreadable] [unreadable]